The endothelium is found in lymphatic vessels, blood vessels, and the lining of the heart (endocardium). The circulatory system is lined with a thin layer of endothelial cells, extending from the heart through the arteries into the capillaries and back again through the veins. Thus, the endothelium plays an important role in vascular function.
The vascular endothelium is believed to play a key role in thrombosis, thrombolysis, lymphocyte homing, soft tissue inflammation and modulation of the immune response. Endothelial cells also play a major role in capillary transport, the regulation of plasma lipids as well as the control of hemostastis.
The recent characterization of the potent peptide vasoconstrictor endothelin-1 (ET-1) has expanded the understanding of the role of the endothelium in the regulation of vascular tone. Endothelin-1 is a 21 amino acid potent vasoconstrictor and growth factor produced by vascular endothelial cells. The vasoconstrictor is derived from amino acids 53-73 of a 203-amino acid precursor, preproendothelin (Bloch et al., J. Biol. Chem. 264:18156-18161 (1989)). The potent vasopressor has a prolonged duration of action. It induces mitogenesis and increases the expression of protooncogenes in vascular smooth muscle cells, fibroblasts, and mesangial cells. Other actions attributed to ET-1 include causing the release of atrial natriuretic factor from atrial cardiocytes in culture and inhibiting the release of renin from glomeruli. The effects of ET-1 on vascular smooth muscle cells implicate it in the pathogenesis of atherosclerosis and hypertension. Thus, knowledge about the regulation of ET-1 gene expression is fundamental to the understanding of the role of the peptide in vascular disease processes. (See Inoue et al., Proc. Natl. Acad. Sci. USA 86:2863-2867 (1989); Yanagisawa et al., Nature 332:411-415 (1988); Komura et al., FEBS Lett. 238:249-252 (1988); and Takuwa et al., J. Biol. Chem. 264:7856-7861 (1989).
During cellular differentiation, different cell types acquire the ability to stably express characteristic sets of genes. The molecular mechanism by which this occurs is poorly understood. In particular, little is known about the mechanisms of expression of endothelial cell-specific genes.
Accordingly, the ability to control gene regulation within the endothelial cells provides the opportunity for modulating vascular and cardiovascular systems.